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Mutational Processes Molding the Genomes of 21 Breast Cancers

Nik-Zainal, Serena; Alexandrov, Ludmil B.; Wedge, David C.; Van Loo, Peter; Greenman, Christopher D.; Raine, Keiran; Jones, David; Hinton, Jonathan; Marshall, John and Stebbings, Lucy A., et al. (2012) In Cell 149(5). p.979-993
Abstract
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of... (More)
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed. (Less)
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Cell
volume
149
issue
5
pages
979 - 993
publisher
Cell Press
external identifiers
  • wos:000304453900006
  • scopus:84861541343
ISSN
1097-4172
DOI
10.1016/j.cell.2012.04.024
project
CREATE Health
language
English
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yes
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ee53961c-1790-4e68-8a34-d61a368145dd (old id 2906969)
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2012-08-01 09:47:28
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2017-11-19 03:03:20
@article{ee53961c-1790-4e68-8a34-d61a368145dd,
  abstract     = {All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.},
  author       = {Nik-Zainal, Serena and Alexandrov, Ludmil B. and Wedge, David C. and Van Loo, Peter and Greenman, Christopher D. and Raine, Keiran and Jones, David and Hinton, Jonathan and Marshall, John and Stebbings, Lucy A. and Menzies, Andrew and Martin, Sancha and Leung, Kenric and Chen, Lina and Leroy, Catherine and Ramakrishna, Manasa and Rance, Richard and Lau, King Wai and Mudie, Laura J. and Varela, Ignacio and McBride, David J. and Bignell, Graham R. and Cooke, Susanna L. and Shlien, Adam and Gamble, John and Whitmore, Ian and Maddison, Mark and Tarpey, Patrick S. and Davies, Helen R. and Papaemmanuil, Elli and Stephens, Philip J. and McLaren, Stuart and Butler, Adam P. and Teague, Jon W. and Jönsson, Göran B and Garber, Judy E. and Silver, Daniel and Miron, Penelope and Fatima, Aquila and Boyault, Sandrine and Langerod, Anita and Tutt, Andrew and Martens, John W. M. and Aparicio, Samuel A. J. R. and Borg, Åke and Salomon, Anne Vincent and Thomas, Gilles and Borresen-Dale, Anne-Lise and Richardson, Andrea L. and Neuberger, Michael S. and Futreal, P. Andrew and Campbell, Peter J. and Stratton, Michael R.},
  issn         = {1097-4172},
  language     = {eng},
  number       = {5},
  pages        = {979--993},
  publisher    = {Cell Press},
  series       = {Cell},
  title        = {Mutational Processes Molding the Genomes of 21 Breast Cancers},
  url          = {http://dx.doi.org/10.1016/j.cell.2012.04.024},
  volume       = {149},
  year         = {2012},
}